View source for 6htc


==Yeast 20S proteasome with human beta2c (S171G) in complex with ONX 0914==
<StructureSection load='6htc' size='340' side='right'caption='[[6htc]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6htc]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HTC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HTC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GQK:(2~{S})-3-(4-methoxyphenyl)-~{N}-[(2~{S},3~{R})-4-methyl-3,4-bis(oxidanyl)-1-phenyl-pentan-2-yl]-2-[[(2~{S})-2-(2-morpholin-4-ylethanoylamino)propanoyl]amino]propanamide'>GQK</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6htc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6htc OCA], [https://pdbe.org/6htc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6htc RCSB], [https://www.ebi.ac.uk/pdbsum/6htc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6htc ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PSA2_YEAST PSA2_YEAST] The proteasome degrades poly-ubiquitinated proteins in the cytoplasm and in the nucleus. It is essential for the regulated turnover of proteins and for the removal of misfolded proteins. The proteasome is a multicatalytic proteinase complex that is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. It has an ATP-dependent proteolytic activity.
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== Publication Abstract from PubMed ==
Subunit-selective proteasome inhibitors are valuable tools to assess the biological function and medicinal relevance of individual proteasome active sites in a specific context. While inhibitors for the beta1c, beta1i, beta5c and beta5i subunits exploit structural differences in the substrate binding channels identified by X-ray crystallography, compounds selectively targeting beta2c or beta2i could not be rationally designed so far due to the high degree of structural similarity of these subunits. Here we report the development, chemical synthesis and biological screening of a compound library that led to the identification of the beta2c- and beta2i-selective compounds LU-002c (4; IC50 beta2c: 8 nM, IC50 beta2i/beta2c: 20-fold) and LU-002i (5; IC50 beta2i: 220 nM, IC50 beta2c/beta2i: 45-fold), respectively. Co-crystal structures with beta2-humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, an elaborate combination of organic syntheses, activity-based protein profiling, yeast mutagenesis and structural biology allowed us to decipher subtle but significant differences of beta2 substrate binding channels and to complete the set of subunit-selective proteasome inhibitors by identifying beta2c- and beta2i-selective compounds.

Structure-based design of inhibitors selective for human proteasome beta2c or beta2i subunits.,Xin BT, Huber E, de Bruin G, Heinemeyer W, Maurits E, Espinal C, Du Y, Janssens M, Weyburne ES, Kisselev A, Florea BI, Driessen C, van der Marel GA, Groll M, Overkleeft HS J Med Chem. 2019 Jan 18. doi: 10.1021/acs.jmedchem.8b01884. PMID:30657666<ref>PMID:30657666</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6htc" style="background-color:#fffaf0;"></div>

==See Also==
*[[Proteasome 3D structures|Proteasome 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Saccharomyces cerevisiae S288C]]
[[Category: Groll M]]
[[Category: Huber EM]]